Dr Alicia Marie Conway

What did your PhD involve?

In 2017 I started my PhD at CRUK National Biomarker Centre researching cancers of unknown primary. Cancers of unknown primary – or CUP – are an under researched group of cancers that are highly aggressive and generally have a poorer prognosis. CUP is difficult to treat because the primary origins of the cancer remain elusive despite the usual diagnostic tests. Research is hampered by a lack of tumour tissue available, as much of it is used up in the diagnostic process. This means little is understood about the molecular drivers of carcinogenesis or biology of CUP.

The aim of my PhD was to evaluate to potential role of blood-based tests in the diagnosis and treatment stratification of CUP. Within the National Biomarker Centre (NBC) we developed a DNA methylation profiling assay designed for cell-free DNA (cfDNA) found within the blood. DNA methylation is an epigenetic mark found on DNA that carries tumour and tissue-specific information. We hypothesised that profiling the circulating cfDNA would enable us to detect the portion of cfDNA arising from the tumour – circulating tumour DNA (ctDNA) – and that the DNA methylation profiles could reveal the potential origins of the cancer.

In collaboration with the Bioinformatics and Biostatistical Team within the NBC, we developed a novel tissue-of-origin classifier called CUPiD. This was trained on publicly available DNA methylation profiles from thousands of known tumour types. To make it applicable to cfDNA we created in silico mixtures of the known tumour methylation profiles diluted with profiles of non-cancer control profiles, mimicking the ctDNA/cfDNA proportions we see in patients with cancer. The resulting trained machine learning classifier was highly sensitive and specific. We tested CUPiD on 143 cfDNA samples from patients with known cancer and found that when CUPiD made a tumour prediction it was correct 96.8% of the time with a sensitivity of 84.6%.

We applied this to a retrospective cohort of 41 patients with CUP and found we could make tissue-of-origin predictions in 32/41 cases; in most cases this diagnosis would have dramatically changed treatment options for the patient and could have sped up diagnosis.

I was awarded the Association of Cancer Physicians Presidents Prize for the work involved in my PhD.

What are you currently working on?

As part of my Academic Clinical Lecturer (ACL) I am attempting to apply a similar approach to other difficult to diagnose cancer types. Through my work in CUP we found that a rare form of biliary tract cancer (intrahepatic cholangiocarcinoma) can be misclassified as CUP – up to 10% of patients in our local data.

Biliary tract cancers (BTCs) are rare and often present at late stages of disease. Diagnosis usually involves an invasive camera test and biopsy which has an up to 25% failure rate, resulting in repeated procedures being required. Having a blood test that could diagnose this group of cancers could significantly speed up diagnosis, negate the need for invasive biopsy and, if sensitive enough, could be used for screening in patients at a high-risk of developing BTC.

I have now secured funding from both the UK cholangiocarcinoma charity, AMMF and the US cholangiocarcinoma foundation (CCF), with additional support from the MCRC Springboard award to evaluate the potential of cfDNA methylation profiling and classifier development for BTC.

What’s the scale of the need that surrounds your research?

There are around 9000 patients diagnosed with CUP in the UK each year and many more patients with suspected cancer who have to undergo multiple, often invasive, investigations. Better diagnosis of cancers where our usual methods often fail or are inconclusive could have a huge impact of patients as well as potentially reduce resource demand and costs to the NHS.

What does this mean for patient outcomes?

Speeding up cancer diagnosis through less invasive means could have a dramatic impact in patient outcomes. Any patient diagnosed with suspected cancer faces an uncertain and difficult journey of tests, including often invasive tests, before meeting an oncologist to discuss potential treatment. For some patients this time can be long and tests inconclusive. Delays in diagnosis not only cause psychological harm to patient but in some cases, patients become more unwell during this time – limiting potential treatment options. Our patients report this period of uncertainty, knowing they have cancer but not what type, as a huge psychological strain. Focusing research efforts on improving diagnosis could not only have a huge benefit for patients but could also reveal potential biomarkers that could be used for screening of patients at high risk of cancer and detecting cancer at earlier stages.

How does it feel to be involved in cancer research?

Day-to-day cancer research can feel slow, but it is so important that we are doing the right research, robustly and in a reproducible way. We learn so much even when something is unexpected or feels like it hasn’t been successful. For me the important step beyond discovery is trying to use our knowledge and understanding to translate this into patient benefit. One of the most amazing parts of the research I do is listening to patients – focusing on the real challenges they face. In Manchester we set up the first UK CUP patient public involvement and engagement group and it has been an extremely positive experience for me and my research. It drives me to use the knowledge and technology we already have to solve the current problems whilst trying to learn and discover more for the future.

What is it like working in a large team of researchers?

My research would not have been possible without the amazing teams of researchers, bioinformaticians, clinicians and clinical staff across CRUK MI and NBC, MCRC, The Christie and The University of Manchester. I have learnt so much from others along the way and one of the best parts of my job is sharing knowledge and results as a team and generating new research ideas for the future.

Useful resources 

Following CUPiD’s arrow: A new blood test to find cancer of unknown primary

A cfDNA methylation-based tissue-of-origin classifier for cancers of unknown primary

Dr Alicia Marie Conway has been awarded the Association of Cancer Physicians Presidents Prize for the best PhD translational research performed by a oncology trainee in the UK as well as being awarded an Early Career Researcher Greater Manchester Cancer Award 2024 for her comprehensive work on CUP.

Dr Alicia-Marie Conway’s PhD was co-funded by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre under the Cancer Precision Medicine theme and CRUK.